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WO2021106231A1 - Composé ayant une activité inhibitrice contre la mutation kras g12d - Google Patents

Composé ayant une activité inhibitrice contre la mutation kras g12d Download PDF

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Publication number
WO2021106231A1
WO2021106231A1 PCT/JP2019/049074 JP2019049074W WO2021106231A1 WO 2021106231 A1 WO2021106231 A1 WO 2021106231A1 JP 2019049074 W JP2019049074 W JP 2019049074W WO 2021106231 A1 WO2021106231 A1 WO 2021106231A1
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Prior art keywords
ring
diazabicyclo
methoxy
compound
octan
Prior art date
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PCT/JP2019/049074
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English (en)
Inventor
Yuichi Kawai
Kazuaki Shibata
Hiroki Asakura
Takao Uno
Takeshi Sagara
Masayuki Nakamura
Yu KOBAYAKAWA
Rhian Sara HOLVEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astex Therapeutics Ltd
Taiho Pharmaceutical Co Ltd
Original Assignee
Astex Therapeutics Ltd
Taiho Pharmaceutical Co Ltd
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Application filed by Astex Therapeutics Ltd, Taiho Pharmaceutical Co Ltd filed Critical Astex Therapeutics Ltd
Priority to TW109141900A priority Critical patent/TW202134243A/zh
Priority to CN202080094483.XA priority patent/CN115003677B/zh
Priority to US17/780,597 priority patent/US20230348495A1/en
Priority to JP2022558819A priority patent/JP7707189B2/ja
Priority to PCT/JP2020/045146 priority patent/WO2021107160A1/fr
Priority to EP20833977.0A priority patent/EP4065583A1/fr
Publication of WO2021106231A1 publication Critical patent/WO2021106231A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound having inhibitory activity against KRAS G12D mutation or a salt thereof, and relates to a pharmaceutical composition comprising the compound as an active ingredient.
  • RAS which is a small monomeric GTP-binding protein having a molecular weight of about 21 kDa, acts as a molecular on/off switch.
  • RAS can bind to GTP by binding to proteins of a guanine nucleotide exchange factor (GEF) (e.g., SOS1), which forces the release of a bound nucleotide, and releasing GDP.
  • GEF guanine nucleotide exchange factor
  • SOS1 guanine nucleotide exchange factor
  • RAS binds to GTP, it becomes activated type (turned on), and recruits and activates proteins necessary for the propagation of other receptors' signals, such as c-Raf and PI 3-kinase.
  • RAS also possesses enzymatic activity with which it cleaves the terminal phosphate of the nucleotide and converts it to GDP. The rate of conversion is usually slow, but can be dramatically sped up by a protein of the GTPase
  • the mainly known members of the RAS subfamily include HRAS, KRAS, and NRAS.
  • mutations of KRAS are observed in many malignant tumors: 95% of pancreatic ductal adenocarcinomas (PDAC), 45% of colon and rectal carcinomas (CRC), and 35% of non-small cell lung carcinomas (NSCLC).
  • PDAC pancreatic ductal adenocarcinomas
  • CRC colon and rectal carcinomas
  • NSCLC non-small cell lung carcinomas
  • the mutations often occur in the glycine residue of KRAS at position 12 in 82% of PDAC, 64% of CRC, 92% of NSCLC.
  • the predominant mutation of KRAS at position 12 in PDAC 39%) and CRC (44%) has been reported to be a mutation into aspartic acid (Non-patent Literature (NPL) 1).
  • NPL Non-patent Literature
  • NPL 1 Nature Reviews Drug Discovery 13 (11), 828-51, 2014
  • NPL 2 Cancer Discov. 6 (3), 316-29, 2016
  • NPL 3 Mol Cancer Res; 13(9), 1325-35, 2015
  • An object of the present invention is to provide a novel compound or a salt thereof that inhibits function of KRAS G12D mutant, and to provide a pharmaceutical composition comprising the compound.
  • the present invention provides the following [1] to [36].
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl;
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; m is 0 or 1.
  • R1 represents hydrogen atom, C1-C6 alkyl, or hydroxyl
  • R2 represents hydrogen atom, halogen atom, alkoxycarbonyl, cyano,or hydroxyalkyl
  • k is 0 to 6.
  • Ring B represents benzene, piperidine, pyrrolidine, cyclohexane, cyclohexene, tetrahydro-2H-pyran, 3,4-dihydro-2H-pyran, or spiro[2.5]octane; wherein the Ring B may be substituted by halogen atom, Cl- C6 alkyl, alkylcarbonyl or oxetanyl; and when the Ring B is pyrrolidine, n is 1 and X is 0 or S, and when the Ring B is not pyrrolidine, n is 0.
  • Ring B represents unsubstituted benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran or 3,4-dihydro- 2H-pyran; and when Ring B is pyrrolidine, n is 1 and X is 0 or S, and when Ring B is not pyrrolidine, n is 0.
  • Y represents an 8- to 10-membered unsaturated bicyclic ring which contains at least one heteroatom selected from the group consisting of N and S, or a 6- to 10-membered aromatic hydrocarbon ring; and wherein the ring may be substituted by halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or 5- to 6- membered unsaturated monocyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0.
  • L represents oxygen atom, or substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, an 8- to 10-membered partially unsaturated ring which contains at least one heteroatoms selected from the group consisting of N, S, and 0; wherein the ring in Z may be substituted by halogen atom, hydroxyl, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, Cl- C3 methoxyalkyl, a substituted or unsubstituted 5- to 6- membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, and which may be substituted by Cl to C3 alkyl, alkylcarbonylalkyl, hydroxyalkyl, dialky
  • L represents oxygen atom
  • m is 0 or 1
  • Z represents C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, an 8- to 10-membered partially saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0; wherein the ring in Z may be substituted by halogen atom, hydroxyl, C1-C6 alkyl, C1-C3 alkoxy, C2-C3 alkynyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl or C1-C6 alkyl which is substituted by 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0 and which may be further substituted by halogen atom.
  • Z represents C3-C6 cycloalkyl or a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and, 0; wherein the ring in Z may be substituted by halogen atom, hydroxyl, cyano, C1-C6 alkyl, C1-C3 alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C1-C6 alkyl which is substituted by 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0 and which may be further substituted by halogen atom.
  • Z represents: cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline or 1,2,3,4-tetrahydroisoquinoline, and which may be substituted by halogen atom, hydroxyl, cyano, C1-C6 alkyl, or C1-C3 alkoxy; alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalky or C1-C6 alkyl which is substituted by 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N and 0 and which may be further substituted by halogen atom.
  • Z represents cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline, or 1,2,3,4- tetrahydroisoquinoline which may be substituted by halogen atom, hydroxyl, C1-C3 alkoxy, methyl, ethyl, isopropanyl, ethylcalbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, methoxyethyl, cyanomethyl, morpholylmethyl, or 3-fluoropyrrolidinylmethyl.
  • Ring A is represented by the formula (3a) or (3b): the Ring B represents benzene, piperidine, or pyrrolidine which may be substituted by halogen atom or C1-C6 alkyl; when Ring B is pyrrolidine, n is 1 and X is 0, and when the Ring B is not pyrrolidine, n is 0;
  • Y represents naphthalene which may be substituted by halogen atom, hydroxyl, C1-C6 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl;
  • Z represents cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline, or 1,2,3,4- tetrahydroisoquinoline which is substituted by halogen atom, hydroxyl, C1-C3 alkoxy, methyl, ethyl, isopropanyl, ethylcalbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, alkoxyalkyl, cyanomethyl, morpholinylmethyl, or 3-fluoropyrrolidinemethyl.
  • a pharmaceutical preparation comprising the compound or a salt thereof according to any one of [1] to [17].
  • a pharmaceutical composition comprising the compound or a salt thereof according to any one of [1] to [17], and a pharmaceutically acceptable carrier.
  • An antitumor agent comprising the compound or a salt thereof according to any one of [1] to [17] as an active ingredient.
  • An antitumor agent for oral administration comprising the compound or a salt thereof according to any one of [1] to [17] as an active ingredient.
  • a method for treating a tumor comprising administering an effective amount of the compound or a salt thereof according to any one of [1] to [17] to a subject in need thereof.
  • An antitumor agent comprising the compound or a salt thereof according to any one of [1] to [17], wherein the agent is administered to a subject in need thereof in combination with a therapeutically effective amount of one or more other antitumor drugs.
  • the antitumor agent of [30], wherein the cancer is at least one selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.
  • squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
  • An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [17], and one or more other antitumor agents as an active ingredient.
  • An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [17] as an active ingredient, which is administered in combination with one or more other antitumor agents.
  • the present invention relates to inhibitors of KRAS G12D (referred to as "KRAS G12D inhibitor").
  • KRAS G12D inhibitor relates to compounds that inhibit the activity of KRAS G12D, pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor.
  • a compound represented by formula (1) or a salt thereof impairs the KRAS function in KRAS G12D mutation-positive cancer cells, thereby showing antitumor action; therefore, a compound represented by formula (1) or a salt thereof can be used as an anti-cancer agent.
  • the compound represented by formula (1) above of the present invention is a novel compound that is nowhere disclosed in any of the literature cited above.
  • examples of the "substituent” include hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, alkyl, hydroxyalkyl, cycloalkyl, C2-4 linear or branched hydrocarbon, alkenyl, alkynyl, alkoxy, benzyl, alkoxyalkyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylaminoalkyl, carboxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a saturated or unsaturated ring, saturated or unsaturated monocyclic or bicyclic ring, aromatic hydrocarbon, and the like.
  • substituent listed above may be the same or different, and the number of them is typically one, two, or three.
  • halogen atom examples include chlorine, bromine, fluorine, and iodine, with chlorine, bromine, fluorine, and iodine being preferable.
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • alkyl include C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, and hexyl.
  • the "alkyl” is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • hydroxyalkyl refers to alkyl mentioned above having at least one hydroxy group (preferably having 1 to 10, and more preferably 1 to 2 hydroxy groups).
  • hydroxyalkyl include C1-C6 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, and 2- hydroxybutyl.
  • the "hydroxyalkyl” is preferably hydroxymethyl or hydroxyethyl.
  • cyanoalkyl refers to alkyl mentioned above having at least one cyano group (preferably having 1 to 10, and more preferably 1 to 2 cyano groups).
  • cyanoalkyl include C1-C6 cyanoalkyl, such as cyanomethyl, cyanoethyl, 1-cyanopropyl, and 2-cyanobutyl.
  • the "cyanoalkyl” is preferably cyanomethyl or cyanoethyl.
  • cycloalkyl refers to monocyclic or polycyclic saturated hydrocarbon.
  • cycloalkyl include C3-C10 cycloalky, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclodecyl, with cyclopropyl, cyclobutyl, and cyclopentyl being preferable, and cyclopropyl, and cyclobutyl being particularly preferable.
  • cycloalkenyl refers to monocyclic or polycyclic unsaturated hydrocarbon containing at least one carbon-carbon double bond (e.g., one to two carbon-carbon double bonds, and preferably one carbon-carbon double bond).
  • Examples of cycloalkenyl include C4-C10 cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclodecenyl, with cyclohexenyl being preferable.
  • unsaturated hydrocarbon refers to linear or branched unsaturated hydrocarbon containing at least one carbon-carbon double bond or triple bond.
  • unsaturated hydrocarbon include C2-C6 unsaturated hydrocarbon, such as vinyl, allyl, methylvinyl, 1-propenyl, butenyl, pentenyl, hexenyl, ethynyl, and 2-propynyl, with C2-4 linear or branched hydrocarbon containing at least one carbon-carbon double bond or triple bond being preferable, and vinyl, allyl, and 1-propenyl being more preferable.
  • alkenyl refers to a linear or branched unsaturated hydrocarbon group containing at least one double bound (e.g., one to two double bonds, and preferably one double bond).
  • alkenyl include C2- C6 alkenyl, such as vinyl, allyl, 1-propenyl, 2-methyl-2- propenyl, isopropenyl, 1-, 2-, or 3-butenyl, 2-, 3- or 4- pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, and 5- hexenyl, with vinyl, allyl, 1-propenyl, and 2-methyl-2- propenyl being preferable.
  • alkynyl refers to linear or branched unsaturated hydrocarbon containing at least one triple bond (e.g., one or two triple bonds, and preferably one triple bond).
  • alkynyl include C2-C6 alkynyl groups, such as ethynyl, 1- or 2-propynyl, 1-, 2-, or 3- butynyl, and 1-methyl-2-propynyl, with ethynyl and 2- propynyl being preferable.
  • alkoxy refers to oxy having alkyl mentioned above.
  • alkoxy include C1-C3 alkoxy, such as methoxy, ethoxy, n-propoxy, and isopropoxy with methoxy and ethoxy being preferable, and methoxy being more preferable.
  • alkoxyalkyl refers to alkyl mentioned above having at least one alkoxy group mentioned above.
  • alkoxyalkyl include C1-C3 alkoxy-C1-C6 alkyl, such as methoxymethyl, ethoxyethyl, methoxyethyl, and methoxypropyl.
  • alkylamino refers to amino having one or two alkyl groups mentioned above. Specific examples of alkylamino include C1-C6 alkylamino, such as methylamino, ethylamino, dimethylamino, diethylamino, and ethylmethylamino, with methylamino and dimethylamino being preferable.
  • alkylaminoalkyl refers to alkyl mentioned above having at least one alkylamino group mentioned above.
  • alkylaminoalkyl include C1-C6 alkylamino-C1-C6 alkyl, such as methylaminomethyl , methylaminoethyl, ethylaminomethyl, and ethylaminopropyl.
  • alkylaminocarbonyl refers to calbonyl mentioned above having at least one alkylamino group mentioned above.
  • alkylaminocarbonyl include Cl- C6 alkylamino-Cl-C6 alkyl, such as methylaminocarbonyl, and ethylaminocarbonyl.
  • dialkylamino refers to amino having two alkyl groups mentioned above.
  • dialkylamino include C2-C12 dialkylamino, such as dimethylamino, diethylamino, di (n-propyl)amino, diisopropylamino, di(n-butyl)amino, diisobutylamino, di (tert-butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino, with dimethylamino being preferable.
  • aromatic hydrocarbon refers to monocyclic or polycyclic aromatic hydrocarbon as being an unsaturated bond-containing ring substituent containing carbon and hydrogen, the monocyclic or polycyclic aromatic hydrocarbon containing 4e+2 number of electrons (e is an integer of 1 or more) in the cyclic n electron system.
  • aromatic hydrocarbon include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, and the like.
  • alkylcarbonyl refers to carbonyl having alkyl mentioned above.
  • alkylcarbonyl include C1-C6 alkylcarbonyl, such as methylcarbonyl , ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n- butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n- pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • alkylcarbonylalkyl refers to alkyl having alkylcarbonyl mentioned above.
  • alkylcarbonylalkyl include C1-C6 alkylcarbonyl, such as methylcarbonylmethyl, ethylcarbonylmethyl, n- propylcarbonylmethyl, isopropylcarbonylmethyl, n- butylcarbonylmethyl, isobutylcarbonylmethyl, tert- butylcarbonylmethyl, n-pentylcarbonylmethyl , isopentylcarbonylmethyl, and hexylcarbonylmethyl, with methylcarbonylmethyl and ethylcarbonylmethyl being preferable.
  • alkylcarbonylaminoalkyl refers to aminoalkyl having alkylcarbonyl mentioned above.
  • alkylcarbonylaminoalkyl include C1-C6 alkylcarbonylaminoalkyl, such as methylcarbonylaminomehtyl and ethylcarbonylaminomehtyl, with methylcarbonylmethyl being preferable.
  • alkoxycarbonyl refers to carbonyl having alkoxy mentioned above.
  • alkoxycarbonyl include C1-C6 alkoxycarbonyl, such as methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl, with methoxycarbonyl being preferable.
  • saturated ring refers to a monocyclic or polycyclic saturated ring containing at least one heteroatom (preferably having 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • saturated ring examples include aziridinyl, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxetanyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolidinyl, oxazolidinyl, and the like, with pyrrolidinyl, piperidinyl, piperazinyl, morpholino, tetrahydrofuranyl, tetrahydro-2H-pyranyl, and oxetanyl being preferable.
  • unsaturated ring refers to a monocyclic or polycyclic, completely or partially unsaturated ring group containing at least one heteroatom (preferably containing 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • unsaturated ring examples include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl , benzothienyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethylenedioxyphenyl , dihydrobenzofuranyl, 1,2,3,4-tetrahydroisoquino
  • CA-CB indicates that the number of carbon atoms of A to B in a certain group.
  • C1-C6 alkyl refers to alkyl having 1 to 6 carbon atoms
  • C6-C14 aromatic hydrocarbon oxy refers to oxy to which C6-C14 aromatic hydrocarbon is bonded.
  • A- to B-membered indicates that the number of atoms (number of ring members) that constitute a ring is A to B. More specifically, "4- to 10-membered saturated ring heterocyclic group” refers to a saturated ring containing 4 to 10 ring members.
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6- membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; m is 0 or 1.
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0.
  • the "saturated 8- to 10-membered N-containing bridged ring” is preferably a saturated monocyclic 8- to 10-membered N- containing bridged ring further containing 1 to 5 heteroatoms selected from N, S, and 0, more preferably a saturated monocyclic 8-membered N-containing bridged ring further containing at least one heteroatom selected from N, S, and 0, and more preferably piperazinyl ring-based, 8-membered N- containing bridged ring, and more preferably diazabicyclo [3.2.1]octane and diazabicyclo [2.2.2]octane, and more preferably diazabicyclo[3.2.1]octane.
  • the "unsaturated 8- to 10-membered N-containing bridged ring” is preferably a unsaturated monocyclic 8- to 10-membered N- containing bridged ring further containing 1 to 5 heteroatoms selected from N, S, and 0, more preferably a unsaturated monocyclic 8-membered N-containing bridged ring further containing at least one heteroatom selected from N, S, and 0, and more preferably piperazinyl ring-based, 8-membered N- containing bridged ring, and more preferably diazabicyclo [3.2.1]oct-6-ene.
  • the substituent in the "substituted 8- to 10-membered N- containing bridged ring” may be, for example, the substituents mentioned above, and is preferably hydrogen atom, C1-C6 alkyl, hydroxyl, halogen atom, alkoxycarbonyl, cyano, nitro or hydroxyalkyl.
  • R 1 may be hydrogen atom or hydroxyl, and preferably hydrogen atom or hydroxyl, and more preferably hydrogen atom.
  • R 2 may be hydrogen atom, halogen atom, alkoxycarbonyl, cyano, nitro, or hydroxyalkyl, and preferably hydrogen atom, alkoxycarbonyl, cyano, nitro, or hydroxyalkyl, and more preferably hydrogen atom.
  • alkoxycarbonyl included in the substituent of Ring A is preferably methoxycarbonyl or ethoxycarbonyl, more preferably methoxycarbonyl.
  • hydroxyalkyl included in the substituents of Ring A is preferably hydroxymethyl or hydroxyethyl, more preferably hydroxymethyl .
  • halogen atom included in substituents of Ring A is preferably fluorine, chlorine, bromine or iodide.
  • k is 0 to 6, and preferably 0 to 5, more preferably 0 to 4, more preferably 0 to 3, more preferably 0 to 2, more preferably 0 or 1, particularly preferably 0.
  • Ring B represents a substituted or unsubstituted, 5- to 6-membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring.
  • the "5- to 6-membered saturated ring having at least one heteroatom selected from the group consisting of N, S, and 0" is preferably a monocyclic 5- to 6-membered saturated ring having 1 to 3 heteroatoms selected from N, S, and 0, more preferably a monocyclic 5- to 6-membered saturated ring having one heteroatom selected from N, S, and 0, more preferably a monocyclic 5- to 6-membered saturated ring having one heteroatom selected from N and 0, and more preferably piperidine, pyrrolidine, or tetrahydro-2H-pyran, and particularly preferably piperidine or pyrrolidine.
  • the "5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0" is preferably a monocyclic 5- to 6-membered unsaturated ring having 1 to 3 heteroatoms selected from N, S, and 0, more preferably a monocyclic 5- to 6-membered unsaturated ring having one heteroatom selected from N, S, and 0, more preferably a monocyclic 5- to 6-membered unsaturated ring having one heteroatom selected from N and 0, and more preferably 2,3-dihydrofuran, 3,4-dihydro-2H-pyran or 4H- pyran, and particularly preferably 3,4-dihydro-2H-pyran.
  • the "4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0." is preferably a monocyclic 4- to 6-membered saturated ring having 1 to 3 heteroatoms selected from N, S, and O, more preferably a monocyclic 4- to 6-membered saturated ring having one heteroatom selected from N, S, and 0, more preferably a monocyclic 4- to 6-membered saturated ring having one heteroatom selected from N and 0, and more preferably oxetanyl, tetrahytdrofuranyl or tetrahydro-2H- pyranyl.
  • the substituent in the "substituted 5- to 6-membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0 may be, for example, the substituents mentioned above, and is preferably, halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to b-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0.
  • halogen atom included in substituents of Ring B is preferably fluorine, chlorine, bromine or iodide.
  • C1-C6 alkyl included in substituents of Ring B is preferably methyl, ethyl, n-propyl, or isopropyl (C1-C3 alkyl), more preferably methyl or ethyl.
  • alkylcarbonyl included in substituents of Ring B is preferably methoxycarbonyl or ethoxycarbonyl, more preferably methoxycarbonyl.
  • the "4- to 6-membered saturated monocyclic ring" in the substituents of Ring B is preferably oxetanyl, tetrahytdrofuranyl or tetrahydro-2H-pyranyl.
  • the "6-membered aromatic hydrocarbon ring" in the "substituted or unsubstituted 6-membered aromatic hydrocarbon ring” is preferably benzene.
  • the substituent in the "substituted 6-membered aromatic hydrocarbon ring” may be, for example, the substituents mentioned above, and is preferably, halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0, and more preferably fluorine, chlorine, methyl, or ethyl .
  • C3-C6 cycloalkyl in the “substituted or unsubstituted C3-C6 cycloalkyl” is preferably cyclobutyl, cyclopentyl, or cyclohexyl, and more preferably cyclohexyl.
  • the substituent in the "substituted C3-C6 cycloalkyl” may be, for example, the substituents mentioned above, and is preferably, a halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0.
  • C3-C6 cycloalkenyl in the “substituted or unsubstituted C3-C6 cycloalkenyl” is preferably cyclopentenyl or cyclohexenyl, and more preferably cyclohexenyl.
  • the substituent in the "substituted C3-C6 cycloalkenyl” may be, for example, the substituents mentioned above, and preferably, halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0, and more prefebly halogen atom or C1-C6 alkyl.
  • the "substituted or unsubstituted C3-C6 cycloalkenyl” is preferably cyclopentenyl, cyclohexenyl or cycloheptenyl, and more preferably cyclohexenyl.
  • the "8- to 10-membered spiro ring" in the “substituted or unsubstituted 8- to 10-membered spiro ring” is preferably spiro[2.5]octane, spiro[3.5]nonane or spiro[4.5]decane, and more preferably spiro[2.5]octane.
  • the substituent in the "substituted or 8- to 10-membered spiro ring” may be, for example, the substituents mentioned above, and preferably halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0.
  • n 1 and X is O or S, and when Ring B is not pyrrolidine, n is 0.
  • Ring B is fused with the pyrimidine ring to form a substituted or substituted bicyclic ring.
  • the bicyclic ring include, but not limited to, quinazoline,
  • the substituent in the "fused with the pyrimidine ring to form a substituted or substituted bicyclic ring” may be, for example, the substituents mentioned above, and preferably halogen atom, Ca-C6 alkyl, C1-C3 alkenyl, alkylcarbonyl, or 4- to 6-membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0, and more preferably fluorine, chlorine, methyl, ethyl, methylcarbonyl, oxetanyl.
  • X represents 0 or S, and preferably 0.
  • Y represents a substituted or unsubstituted, 6- to 10-membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring.
  • the "6- to 10-membered unsaturated bicyclic ring" in the “substituted or unsubstituted, 6- to 10-membered unsaturated bicyclic ring” is preferably a bicyclic 6- to 10-membered unsaturated ring containing 1 to 5 heteroatoms selected from N, S and 0, more preferably a bicyclic 6- to 10- membered unsaturated ring containing 1 to 3 heteroatoms selected from N and S, and more preferably, benzo[b]thiphene, isoguinoline, thieno[2,3-c]pyridine, indole, or indazole.
  • the substituent in the "substituted 6- to 10-membered unsaturated bicyclic ring” may be, for example, the substituents mentioned above, halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or 5- to 6-membered unsaturated monocyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, more preferably halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or thiophenyl, and more preferably bromine, fluorine, chlorine, iodine, hydroxyl, amino, methyl, vinyl, ethynyl or thiophenyl.
  • the "6- to 10-membered aromatic hydrocarbon ring” is preferably benzene or naphthalene, and more preferably naphthalene.
  • the substituent in the "substituted 6-membered aromatic hydrocarbon ring” may be, for example, the substituents mentioned above, halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or 5- to 6-membered unsaturated monocyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, and more preferably halogen atom, hydroxyl, amino, C1-C6 alkyl, C2- C3 alkenyl, C2-C3 alkynyl or thiophenyl.
  • halogen atom included in the substituents of Y is preferably fluorine, chlorine, bromine, or iodide.
  • C1-C6 alkyl included in the substituents of Y is preferably methyl, ethyl, n-propyl, or isopropyl (C1-C3 alkyl), more preferably methyl or ethyl.
  • the "C2-C3 alkenyl” included in the substituents of Y is preferably vinyl, 1-propenyl, allyl, and more preferably vinyl.
  • C2-C3 alkynyl included in the substituents of Y is preferably ethynyl or 1-propynyl, and more preferably ethynyl .
  • the "5- to 6-membered unsaturated monocyclic ring” is preferably 5- to 6-membered unsaturated monocyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, and more preferably thiophenyl.
  • L represents an oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl.
  • C2-C3 alkynyl is preferably ethynyl or 1-propynyl, and more preferably ethynyl.
  • the substituent in the "substituted C2-C3 alkenyl" represented by L may be, for example, the substituents mentioned above, and preferably dimethylaminomethyl or dimethylaminocarbonylmethyl.
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0.
  • cyanoalkyl is preferably cyanomethyl or cyanoethyl, and more preferably cyanomethyl.
  • alkylcarbonylaminoalkyl is preferably methylcarbonylaminomehtyl, ethylcarbonylaminomehtyl, or ethylcarbonylaminoehtyl, and more preferably methylcarbonylaminomehtyl.
  • alkylaminocarbonyl is preferably dimethylaminocarbonyl, methylaminocarbonyl or diethylaminocarbonyl, and more preferably dimethylaminocarbonyl.
  • alkylaminoalkyl in the "substituted or unsubstituted alkylaminoalkyl” is preferably dimethylaminomethyl, dimethylaminoethyl, methylaminoethyl, or diethylaminoethyl, and more preferably dimethylaminomethyl or dimethylaminoethyl.
  • C3-C6 cycloalkyl in the "substituted or unsubstituted C3-C6 cycloalkyl” is preferably cyclopropyl, cyclobutyl, cyclopentyl, and more preferably cyclopropyl or cyclobutyl, and more preferably cyclopropyl.
  • the substituent in the "substituted C3-C6 cycloalkyl” may be, for example, the substituents mentioned above, and is preferably halogen atom, hydroxyl, C1-C6 alkyl, C1-C3 alkoxy, a substituted or unsubstituted 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, and which may be substituted by C1 to C3 alkyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, or cyanoalkyl, and more preferably halogen atom, hydroxyl, methoxy, methyl, ethyl, isopropanyl, ethylcalbonylmethyl , hydroxyethyl, dimethylamino, dimethylaminomethyl, cyanomethyl, morpholylmethyl, or 3-fluoropyrrolidinyl
  • the "5- to 6-membered saturated ring" in the “substituted or unsubstituted 5- to 6-membered saturated ring” is preferably a 5- to 6- membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, and more preferably a 5- to 6-membered saturated ring containing 1 to 3 heteroatoms selected from N, and 0, and more preferably tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, piperidinyl, morpholiyl, or piperazinyl.
  • the substituent in the "substituted 5- to 6-membered saturated ring” may be, for example, the substituents mentioned above, and is preferably halogen atom, hydroxyl, C1-C6 alkyl, C1-C3 alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, or cyanoalkyl, and more preferably halogen atom, hydroxyl, methoxy, methyl, ethyl, isopropanyl, ethylcalbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, or metoxyethyl, cyanomethyl.
  • halogen atom is preferably morpholylmethyl, or 3-fluoropyrrolidinylmethyl.
  • the "8- to 10-membered partially unsaturated ring" in the “substituted or unsubstituted 8- to 10-membered partially unsaturated ring” is preferably 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, and more preferably 8- to 10-membered partially unsaturated ring which contains one heteroatom selected from the group consisting of N, S and 0, and more preferably isoindoline or 1,2,3,4-tetrahydroisoquinoline.
  • the substituent in the "substituted 8- to 10-membered partially unsaturated ring” is preferably C1-C6 alkyl, and more preferably methyl or ethyl, and more preferably methyl.
  • substituted 8- to 10-membered partially unsaturated ring is preferably substituted or unsubstituted 8- to 10- membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N ' , S and 0, and more preferably 2-methylisoindoline or 2-methyl- 1,2,3,4-tetrahydroisoquinoline.
  • halogen atom included in the substituents of Z is preferably fluorine, chlorine, bromine, or iodide.
  • C1-C6 alkyl included in the substituents of Z is preferably methyl, ethyl, propyl or isopropanyl, and more preferably methyl, ethyl or isopropanyl.
  • the "C1-C3 alkoxy" included in the substituents of Z is preferably methoxy or ethoxy, and more preferably methoxy.
  • alkylcarbonylalkyl included in the substituents of Z is preferably methylcarbonylmethyl, ethylcarbonylmethyl or ethylcarbonylethyl, and more preferably ethylcarbonylmethyl.
  • the "hydoroxyalkyl” included in the substituents of Z is preferably hydroxymethyl, hydroxyethyl or hydroxylpropyl, and more preferably hydroxymethyl.
  • alkoxyalkyl included in the substituents of Z is preferably methoxyethyl, methoxymethyl or ethoxyethyl, and more preperably methoxyethyl.
  • cyanoalkyl included in the substituents of Z is preferably cyanomethyl or cyanothyl, and more preferably cyanomethyl.
  • alkylcarbonylaminoalkyl included in the substituents of Z is preferably methylcarbonylaminomehtyl, ethylcarbonylaminomehtyl, or ethylcarbonylaminoehtyl, and more preferably methylcarbonylaminomehtyl.
  • alkylaminocarbonyl included in the substituents of Z is preferably dimethylaminocarbonyl, methylaminocarbonyl or diethylaminocarbonyl, and more preferably dimethylaminocarbonyl.
  • alkylaminoalkyl included in the substituents of Z is preferably dimethylaminoethyl, methylaminoethyl , or diethylaminoethyl, and more preferably dimethylaminoethyl.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein the Ring D is represented by any one of the formulae (2a) to (2c) which may be substituted by R1 and R2:
  • R1 represents hydrogen atom, C1-C6 alkyl, or hydroxyl
  • R2 represents hydrogen atom, alkoxycarbonyl , cyano,or hydroxyalkyl
  • k is 0 to 1
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5 to 6 membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; and m is 0 or 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A is represented by the formula (3a) or (3b):
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl;
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl , alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5 to 6 membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; and m is 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents
  • a 6- to 10-membered aromatic hydrocarbon ring wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one hetero atom selected from N, S, and 0; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5 to 6 membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; and m is 0 or 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran, 3,4-dihydro-2H-pyran, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one hetero atom selected from N, S, and 0; and when the Ring B is pyrrolidine, n is 1 and X is 0 or S, and when the Ring B is not pyrrolidine, n is 0;
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; and m is 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents
  • a 5- to 6-membered saturated or unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one hetero atom selected from N, S, and 0; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl , alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; when L is C2-C3 alkynyl, Z is alkylaminocarbonyl or alkylaminoalkyl; and m is 0 or 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents piperidine, pyrrolidine, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0,and when the Ring B is pyrrolidine, n is 1 and X is 0 or S, and when the Ring B is not pyrrolidine, n is 0;
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl , alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and
  • a 6-membered aromatic hydrocarbon ring C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents 6- to 10-membered aromatic hydrocarbon ring, which may be substituted by halogen atom, hydroxyl, amino, Cl-6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or thiophenyl;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl;
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl , alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of
  • L is C2-C3 alkynyl
  • Z is alkylaminocarbonyl or alkylaminoalkyl
  • m is 0 or 1.
  • the compound or a salt thereof of the present invention is more preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and
  • a 6-membered aromatic hydrocarbon ring C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents benzene or naphthalene, which may be substituted by halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or thiophenyl;
  • L represents oxygen atom, or a substituted or unsubstituted C2-C3 alkynyl
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and
  • a 6-membered aromatic hydrocarbon ring C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5 to 6 membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; and m is 0 or 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring D represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom
  • Z represents a substituted or unsubstituted C3-C6 cycloalkyl; wherein the ring in Z may be substituted by halogen atom, hydroxyl, cyano, C1-C6 alkyl, C1-C3 alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C1-C6 alkyl which is substituted by 5- to b-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, and which may be further substituted by halogen atom; and m is 1.
  • the compound or a salt thereof of the present invention is preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A represents a substituted or unsubstituted, saturated or unsaturated 8- to 10-membered N-containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and 0;
  • Ring B represents a substituted or unsubstituted, 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and 0, a 6-membered aromatic hydrocarbon ring, C3-C6 cycloalkyl ring, C3-C6 cycloalkenyl or an 8- to 10-membered spiro ring, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom
  • Z represents a substituted or unsubstituted, a 5- to 6- membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; wherein the ring in Z may be substituted by halogen atom, hydroxyl, cyano, C1-C6 alkyl, C1-C3 alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C1-C6 alkyl which is substituted by 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, and which may be further substituted by halogen atom; and m is 0 or 1.
  • the compound or a salt thereof of the present invention is more preferably a compound represented by formula (1) or a salt thereof, wherein :
  • Ring D is represented by the formula (3a) or (3b):
  • Ring B represents:
  • a 6- to 10-membered aromatic hydrocarbon ring wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one hetero atom selected from N, S, and 0; n is 0 or 1;
  • X is 0 or S
  • Y represents a substituted or unsubstituted, 6- to 10- membered unsaturated monocyclic or bicyclic ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or 6- to 10-membered aromatic hydrocarbon ring;
  • L represents oxygen atom
  • Z represents cyanoalkyl, alkylcarbonylaminoalkyl , alkylaminocarbonyl, alkylaminoalkyl, a substituted or unsubstituted, C3-C6 cycloalkyl, a 5 to 6 membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0, or an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S and 0; and m is 1.
  • the compound or a salt thereof of the present invention is more preferably a compound represented by formula (1) or a salt thereof, wherein:
  • Ring A is represented by the formula (3a);
  • Ring B represents benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran, or 3,4-dihydro-2H-pyran, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0, and when Ring B is pyrrolidine, n is 1 and X is 0 or S and when
  • Ring B is not pyrrolidine, n is 0;
  • Y represents benzene or naphthalene, which may be substituted by halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl or C2-C3 alkynyl;
  • L represents oxygen atom
  • Z represents a substituted or unsubstituted C3-C6 cycloalkyl, wherein the ring in Z may be substituted by halogen atom, hydroxyl, cyano, C1-C6 alkyl, C1-C3 alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C1-C6 alkyl which is substituted by 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and 0, and which may be further substituted by halogen atom; and m is 1.
  • the compound or a salt thereof of the present invention is still more preferably a compound represented by formula (1) or a salt thereof, wherein
  • Ring A is represented by the formula (3a)
  • Ring B represents benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran, or 3,4-dihydro-2H-pyran, wherein the Ring B is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein the Ring B in the bicyclic ring may be substituted by halogen atom, C1-C6 alkyl, alkylcarbonyl or 4- to 6- membered saturated monocyclic ring which contains at least one heteroatom selected from N, S, and 0, and when Ring B is pyrrolidine, n is 1 and X is 0 or S and when
  • Ring B is not pyrrolidine, n is 0;
  • Y represents benzene or naphthalene, which may be substituted by halogen atom, hydroxyl, amino, C1-C6 alkyl, C2-C3 alkenyl or C2-C3 alkynyl;
  • L represents oxygen atom
  • Z represents a substituted or unsubstituted cyclopentane or cyclobutane, wherein the ring in Z may be substituted by dimethylamino, dimethylaminomethyl, morpholinylmethyl, methylpyrrolidine or 3-fluoropyrrolidinemethyl; and m is 1.
  • Examples of specific compounds of the present invention include, but are not limited to, the compounds produced in the Examples below.
  • Examples of preferable compounds of the present invention include the following:
  • the compound represented by formula (1) of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known in the art, for example, through the following production methods or reaction steps described in the Examples.
  • the production methods are not limited to these methods and reaction scheme as long as a product of interest can be obtained.
  • An intermediate product or a final product obtained in each step can be subjected to the subsequent step after, or without, isolation and purification by known separation and purification methods, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a protecting group that can be easily converted to the functional group can be introduced if it is effective in each step, or so as to change the order of the steps.
  • the protecting group used herein may be the protecting groups etc. used in the method disclosed in "Protective Groups in Organic Synthesis," 5th edition, Greene and Wuts, John Wiley & Sons Inc., 2014.
  • the protecting group may be appropriately selected according to the reaction conditions of each step. After introducing a protecting group and performing reaction, the protecting group is optionally removed to thus yield a desired compound.
  • a process for preparing a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof which comprises following scheme:
  • the compound of formula (4) is subjected to a coupling reaction with the compound of formula (5) to produce the compound of formula (6).
  • the compounds of formula (5) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (4) with a compound of formula (5) and suitable base in a suitable solvent at a suitable temperature.
  • suitable base is N,N-diisopropylethylamine.
  • suitable solvents is N,N-dimethylacetamide.
  • the amount of a compound of formula (5) used herein is usually 1 to 100 moles, and preferably 1 to 10 moles, per mole of the compound represented by formula (4).
  • the amount of the base used is usually 1 to 100 moles, and preferably 1 to 20 moles, per mole of the compound represented by formula (4).
  • the reaction temperature generally ranges from 0 to 100°C, preferably 0 to 60°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (6) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography. [0161]
  • the compound of formula (6) is subjected to a coupling reaction with the compound of formula (7) to produce the compound of formula (8).
  • the compounds of formula (7) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (6) with a compound of formula (7) and a suitable catalyst, a suitable base in a suitable solvent at a suitable temperature.
  • Suitable catalysts are Ruphos Pd G3 or Ruphos Pd G4.
  • suitable base are sodium carbonate, potassium carbonate, potassium phosphate and cesium carbonate.
  • suitable solvents are tetrahydrofuran, 1,2- dimethoxyethane and 1,4-dioxane.
  • the amount of a compound of formula (7) used is usually 1 to 100 moles, and preferably 1 to 20 moles, per mole of the compound represented by formula (6).
  • the amount of the catalyst used is usually 0.0001 to 1 moles, and preferably 0.001 to 0.5 moles, per mole of the compound represented by formula (6).
  • the amount of the ligand used is usually 0.0001 to 4 moles, and preferably 0.001 to 2 moles, per mole of the compound represented by formula (6).
  • the amount of the base used is usually 0.1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (6).
  • the reaction temperature generally ranges from 0 to 200°C, preferably room temperature to 150°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (8) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography. [0168]
  • Examples of the protecting group represented by Pi in the compound of formula (8) include benzyloxycarbonyl (Cbz).
  • the process typically comprises, reacting a compound of formula (8) with a suitable catalyst in a suitable solvent at a suitable temperature and a suitable pressure under hydrogen atmosphere.
  • Suitable catalysts are palladium on carbon, and palladium hydroxide on carbon.
  • suitable solvents are methanol and ethanol.
  • the amount of the catalyst used is usually 1 to 300 wt%, and preferably 1 to 100 wt%, per mole of the compound represented by formula (8).
  • the reaction temperature generally ranges from 0 to 100°C, preferably room temperature to 60°C.
  • the reaction pressure generally ranges from 1 to 20 atm, preferably 1 to 5 atm.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (9) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • the compound of formula (9) is subjected to a coupling reaction with the compound of formula (10) to produce the compound of formula (1).
  • the compounds of formula (10) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (9) with a compound of formula (10) and a suitable catalyst, a suitable base in a suitable solvent at a suitable temperature.
  • Suitable catalysts are PdCl2dppf, RUPHOS Pd G4 and Pd 2 dba 3 with suitable ligand (such as BINAP, Xantphos or Davephos).
  • suitable base are NaOtBu, LHMDS, K 2 CO 3 and CS 2 CO 3 .
  • suitable solvents are toluene, 1,4- dioxane and THF.
  • the amount of a compound of formula (10) used is usually 1 to 100 moles, and preferably 1 to 20 moles, per mole of the compound represented by formula (9).
  • the amount of the catalyst used is usually 0.0001 to 1 moles, and preferably 0.001 to 0.6 moles, per mole of the compound represented by formula (9).
  • the amount of the ligand used is usually 0.0001 to 4 moles, and preferably 0.001 to 2 moles, per mole of the compound represented by formula (9).
  • the amount of the base used is usually 0.1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (9).
  • the reaction temperature generally ranges from 0 to 200°C, preferably room temperature to 150°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (1) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • Step e Condensation reaction (wherein D, B, L, m, n, X, Y, Z are as defined above).
  • the compound of formula (9) is subjected to a condensation with the compound of fomula(ll) to produce the compound of formula (1).
  • the compounds of formula (11) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (9) with a compound of formula (11) and a suitable condensation reagent, a suitable base in a suitable solvent at a suitable temperature.
  • condensation reagents are l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or 1-[bis(dimethylamino)methylene]- lH-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate.
  • suitable base are triethylamine and N,N-diisopropylehtylamine.
  • suitable solvents are N,N-dimethylformamide and tetrahydrofuran.
  • the amount of the compound of formula (11) used is usually 1 to 100 moles, and preferably 1 to 10 moles, per mole of the compound represented by formula (9).
  • the amount of condensation reagents used is usually 1 to 100 moles, and preferably 1 to 10 moles, per mole of the compound represented by formula (9).
  • the amount of the base used is usually 1 to 100 moles, and preferably 1 to 10 moles, per mole of the compound represented by formula (9).
  • the reaction temperature generally ranges from 0 to 200°C, preferably room temperature to 150°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (1) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • the compound of formula (12) is subjected to a coupling reaction with the compound of formula (5) to produce the compound of formula (13).
  • the compounds of formula (5) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (12) with a compound of formula (5) and suitable base in a suitable solvent at a suitable temperature.
  • a suitable base is N,N-diisopropylethylamine.
  • suitable solvent is N,N-dimethylacetamide.
  • the amount of a compound of formula (5) used is usually 1 to 100 moles, and preferably 1 to 10 moles, per mole of the compound represented by formula (12).
  • the amount of the base used is usually 1 to 100 moles, and preferably 1 to 20 moles, per mole of the compound represented by formula (12).
  • the reaction temperature generally ranges from 0 to 100°C, preferably 0 to 60°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (13) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • the compound of formula (13) is subjected to a coupling reaction with the compound of formula (7) to produce the compound of formula (14).
  • the compounds of formula (7) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (13) with a compound of formula (7) and a suitable catalyst, a suitable base in a suitable solvent at a suitable temperature.
  • Suitable catalysts are Ruphos Pd G3 and Ruphos Pd G4.
  • suitable base are sodium carbonate, potassium carbonate, potassium phosphate and cesium carbonate.
  • suitable solvents are tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane.
  • the amount of a compound of formula (7) used is usually 1 to 100 moles, and preferably 1 to 20 moles, per mole of the compound represented by formula (13).
  • the amount of the catalyst used is usually 0.0001 to 1 moles, and preferably 0.001 to 0.5 moles, per mole of the compound represented by formula (13).
  • the amount of the ligand used is usually 0.0001 to 4 moles, and preferably 0.001 to 2 moles, per mole of the compound represented by formula (13).
  • the amount of the base used is usually 0.1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (13).
  • the reaction temperature generally ranges from 0 to 200°C, preferably room temperature to 150°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 min to 4 days.
  • the thus-obtained compound of formula (14) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • Ti represents a metal or metaloid residue (such as boronic acid or pinacol boronate)
  • A, B, L, m, n, X, Y, and Z are as defined above.
  • the compound of formula (14) is subjected to a coupling reaction with the compound of formula (15) to produce the compound of formula (1).
  • the compounds of formula (15) are either commercially available, or may be prepared using methods identical to or analogous to those described in the examples.
  • the process typically comprises, reacting a compound of formula (14) with the compound of formula (15) and a suitable catalyst in a suitable solvent at a suitable temperature.
  • suitable catalysts are [1,1'- bis (diphenylphosphino)ferrocene]palladium (II) dichloride, tetrakistriphenylphosphine palladium and tris (dibenzylideneacetone)dipalladium (0) with a suitable ligand (such as triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).
  • Suitable base are sodium carbonate, potassium carbonate and potassium phosphate.
  • suitable solvents are tetrahydrofuran, 1,2-dimethoxyethane and 1,4- dioxane with water.
  • the amount of an amine of formula (VII) used is usually 1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (14).
  • the amount of the catalyst used is usually 0.0001 to 1 moles, and preferably 0.001 to 0.5 moles, per mole of the compound represented by formula (14).
  • the amount of the ligand used is usually 0.0001 to 4 moles, and preferably 0.001 to 2 moles, per mole of the compound represented by formula (14).
  • the amount of the base used is usually 0.1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound represented by formula (14).
  • the amount of the base used is generally 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by formula (14).
  • the reaction temperature generally ranges from 0 to 200°C, preferably room temperature to 150°C.
  • the reaction time generally ranges from 5 minutes to 7 days, preferably 30 minutes to 4 days.
  • the thus-obtained compound of formula (1) can be subjected to the subsequent step after or without isolation or purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • any of the isomers and mixtures thereof are included within the scope of the compound of the present invention unless otherwise specified.
  • the compound of the present invention has optical isomers, racemic mixtures and the optical isomers separated from a racemic mixture are also included within the scope of the compound of the present invention unless otherwise specified
  • the compound or a salt thereof of the present invention may be in the form of amorphous or crystals. Single crystals and polymorphic mixtures are included within the scope of the compound or a salt thereof of the present invention. Such crystals can be produced by crystallization according to a crystallization method known in the art.
  • the compound or a salt thereof of the present invention may be a solvate (e.g., a hydrate) or a non-solvate. Any of such forms are included within the scope of the compound or a salt thereof of the present invention.
  • Compounds labeled with an isotope e.g., 2 H, 3 H, 13 C, 14 C, 35 S, 125 I
  • an isotope are also included within the scope of the compound or a salt thereof of the present invention.
  • the salts of the compound of the present invention refer to any pharmaceutically acceptable salts; examples include base addition salts and acid addition salts.
  • the present invention provides a medicament containing the compound of the present invention or a salt thereof as an active ingredient. Furthermore, the present invention relates to use of the compound of the present invention or a salt thereof for the manufacture of a medicament. Further, the present invention provides the use as medicaments of the compound of the present invention or a salt thereof. Further, provided is the compound of the present invention or a salt thereof for use as a medicament.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier.
  • the medicament or pharmaceutical composition is a therapeutic agent for the KRAS-related diseases, in a more preferred embodiment, the medicament or pharmaceutical composition is an antitumor agent.
  • KRAS-related diseases refer to a "KRAS G12D- associated disease or disorder".
  • the "KRAS G12D-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a KRAS G12D mutation.
  • a non-limiting example of a KRAS G12D- associated disease or disorder is a KRAS G12D-associated cancer.
  • KRAS G12D refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human KRAS is based on the amino acid sequence identified by, for example, GenPept ID NP_004976.
  • KRAS G12D inhibitor refers to compounds of the present invention that are represented by formula (1) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS G12D.
  • the KRAS G12D inhibitors of the present invention bind to KRAS G12D by forming a ionic interaction with the aspartic acid at position 12 of inactive KRAS (GDP), thus preventing conversion of inactive KRAS (GDP) to active KRAS (GTP) and inhibiting downstream signaling.
  • the present invention comprises administering an effective amount of the compound of the present invention or a salt thereof to a subject to provide a KRAS G12D mutation activity suppression method. Further, the present invention comprises administering a therapeutically effective amount of the compound of the present invention or a salt thereof to a subject to provide a method of treating KRAS-related diseases.
  • a method of treating KRAS-related diseases is a method of treating tumors.
  • the subjects include human or non-human animal in need of the method.
  • the "effective amount" of the compound according to an embodiment of the present invention refers to an amount of the compound which is sufficient to achieve a biological response or therapeutic response of a subject, such as causing reduction or prevention of an activity of enzyme or protein; or improving a symptom, alleviating a medical state, delaying or retarding progression of disorder, or preventing a disease (therapeutically effective amount).
  • the "subject" includes a mammal and a nonmammal.
  • a mammal include, but not limited to, a human, a chimpanzee, an anthropoid, a monkey, a cow, a horse, a sheep, a goat, a pig, a rabbit, a dog, a cat, a rat, a mouse, a Cavia porcellus, a hedgehog, a kangaroo, a mole, a boar, a bear, a tiger and a lion.
  • a nonmammal include, but not limited to, birds, fishes and reptiles.
  • the subject is a human, and may be a human who has been diagnosed to need a treatment for the symptom, the medical state or disease as disclosed herein.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer having a KRAS G12D mutation.
  • the subject has a tumor that is positive for a KRAS G12D mutation.
  • a medicament, a .pharmaceutical composition or a pharmaceutical preparation comprising the compound or pharmaceutically acceptable salt thereof of the present invention may be provided.
  • an anti-tumor agent comprising the compound or pharmaceutically acceptable salt thereof of the present invention as an active ingredient may be provided.
  • the compound or a salt thereof of the present invention also encompasses prodrugs thereof.
  • a prodrug refers to a compound that can be converted to the compound or a salt thereof of the present invention through a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that can be converted to the compound or a salt thereof of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like; or a compound that can be converted to the compound or a salt thereof of the present invention by hydrolysis or the like with gastric acid or the like.
  • the prodrug may be compounds that can be converted to the compound or a salt thereof of the present invention under physiological conditions, such as those described in Iyakuhin no Kaihatsu, "Development of Pharmaceuticals," Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198.
  • a pharmaceutical carrier can be added, if required, thereby forming a suitable dosage form according to prevention and treatment purposes.
  • the dosage form include oral preparations, injections, suppositories, ointments, inhalations, patches, and the like.
  • Such dosage forms can be formed by methods conventionally known to a person skilled in the art.
  • various conventional organic or inorganic carrier materials used as preparation materials may be blended as an excipient, binder, disintegrant, lubricant, or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, buffer, or soothing agent in liquid preparations.
  • pharmaceutical preparation additives such as antiseptics, antioxidants, colorants, sweeteners, and stabilizers, may also be used, if required.
  • a medicament, a pharmaceutical composition or a pharmaceutical preparation for oral administration or an oral solid preparation comprising the compound or pharmaceutically acceptable salt thereof of the present invention may be provided.
  • an anti-tumor agent for oral administration comprising the compound or pharmaceutically acceptable salt thereof of the present invention as an active ingredient may be provided.
  • Oral solid preparations or a medicament, a pharmaceutical composition, an anti-tumor agent or a pharmaceutical preparation for oral administration are prepared as follows. After an excipient is added optionally with a binder, disintegrant, lubricant, colorant, taste-masking or flavoring agent, etc. to the compound or a salt thereof of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods.
  • Oral solid preparations are prepared as follows. After an excipient is added optionally with a binder, disintegrant, lubricant, colorant, taste-masking or flavoring agent, etc. to the compound or a salt thereof of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods. [0233]
  • a pH regulator, a buffer, a stabilizer, an isotonizing agent, a local anesthetic, and the like may be added to the compound of the present invention; and the mixture may be formulated into a subcutaneous, intramuscular, or intravenous injection according to an ordinary method.
  • the amount of the compound of the present invention to be incorporated in each of such dosage unit forms depends on the condition of the patient to whom the compound is administered, the dosage form, etc. In general, for an oral agent, the amount of the compound is preferably about 0.05 to 1000 mg per dosage unit form. For an injection, the amount of the compound is preferably about 0.01 to 500 mg per dosage unit form, and for a suppository, the amount of the compound is preferably about 1 to 1000 mg per dosage unit form.
  • the daily dose of the medicine in such a dosage form varies depending on the condition, body weight, age, sex, etc. of the patient, and cannot be unconditionally determined.
  • the daily dose for an adult (body weight: 50 kg) of the compound of the present invention may be generally about 0.05 to 5000 mg, and preferably 0.1 to1000 mg.
  • the effective amount or administration regimen of the compound of the formula (1) of the present invention or a pharmaceutically acceptable salt thereof administered to the above subject can be suitably determined by a person skilled in the art depending on, for example, species, symptom, weight, age, or sex, of the subject.
  • the subject is an adult human, it is usually administered at 0.05 to 5000 mg, and preferably 0.1 to 1000 mg per day in terms of the amount of the compound of the formula (1) of the present invention.
  • the compound or a salt thereof of the present invention has excellent KRAS inhibitory activity against KRAS G12D mutation-positive cancer cells, and also has excellent selectivity for KRAS G12D mutation than wild-type KRAS normal cells. Therefore, the compound or a salt thereof of the present invention is useful as an antitumor agent against KRAS G12D mutation-positive cancer cells, and has the advantage of fewer side effects.
  • the compound or a salt thereof of the present invention inhibits the KRAS function and is useful as a pharmaceutical preparation for preventing and treating KRAS-associated signaling-related diseases.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing a pharmaceutical composition may be provided.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing an anti-tumor agent may be provided.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing an anti-tumor agent for oral administration may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use as medicament may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use in the prevention and/or treatment of tumor may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use in the prevention and/or treatment of tumor by oral administration may be provided.
  • a method for preventing and/or treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention to a subject in need thereof.
  • an antitumor agent which is administered to a subject in need thereof in combination with a pharmaceutically effective amount of one or more other antitumor drugs may be provided.
  • a method for preventing and/or treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention to a subject in need thereof.
  • an antitumor agent which is administered to a subject in need thereof in combination with a pharmaceutically effective amount of one or more other antitumor drugs may be provided.
  • KRAS is involved in various signaling transduction as RAS-associated signaling; KRAS mainly activates, but is not limited to, RAF, PI3K, RAL-GEF, and the like.
  • the diseases include diseases whose incidence can be reduced, and whose symptoms can be remitted, relieved, and/or completely cured by deleting, suppressing, and/or inhibiting their functions.
  • cancers targeted in the present invention include, but are not particularly limited to, head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., non-small-cell lung cancer, small-cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myel
  • Preferable examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer colorectal cancer and uterine cancer.
  • squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
  • adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.
  • tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer leukemia or uterine cancer.
  • a subject suffering from any of the disease selected from the above does not have to have KRAS G12D mutant protein. In a preferred embodiment, a subject suffering from any of the disease selected from the above has KRAS G12D mutant protein.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of the present invention, and one or more other antitumor agents as an active ingredient may be provided.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient, which is administered in combination with one or more other antitumor agents may be provided.
  • use of the compound of the present invention or a salt thereof and one or more other antitumor agents for the manufacture of an antitumor agent may be provided.
  • use of the compound of the present invention or a salt thereof for the manufacture of an antitumor agent, which is administered in combination with one or more other antitumor agents may be provided.
  • the combination of a compound of the present invention or a salt thereof and one or more other antitumor agents for use in the treatment of tumors may be provided. In one embodiment, may be provided. In one embodiment, the compound or pharmaceutically acceptable salt thereof of the present invention for use in the treatment of tumor, which is administered in combination with one or more other antitumor agents may be provided.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention, and one or more other antitumor agents to a subject in need thereof may be provided.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention, which is administered in combination with one or more other antitumor agents to a subject in need thereof may be provided.
  • a method for modulating an activity of Ras protein including human KRAS G12D mutant protein which comprises contacting the Ras protein with an effective amount of the compound of the present invention.
  • Examples of the activity to be modulated includes GTPase activity, nucleotide exchange, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, Ras, e.g., KRAS, localization in a cell, post-translational processing of Ras, e.g., KRAS, and posttranslation modification of Ras, e.g., KRAS, and preferably include KRAS localization in a cell, post-translational processing of KRAS, and posttranslation modification of KRAS.
  • the "modulating" may be increasing or decreasing the activity of the Ras, e.g., KRAS protein.
  • Ras e.g., KRAS
  • protein exists in a living cell, such as a living cell which forms a part of a living object.
  • treatment includes treatment carried out for the purpose of curing or ameliorating the disease, or for the purpose of suppressing the progression or recurrence of the disease or alleviating the symptoms.
  • tetramethylsilane was used as the internal reference.
  • measurement was performed using an NMR solvent as the internal reference. All d values are indicated in ppm.
  • Microwave reaction was performed using an Initiator (trademark) manufactured by Biotage. Reverse phase preparative HPLC column chromatography was performed at the following conditions.
  • Step 1 benzyl 4- (8-(tert-butoxycarbonyl)-3,8- diazabicyclo [3.2.1]octan-3-yl)-2-chloro-5,8- dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate
  • Step 2 benzyl 4- (8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-((1-
  • Step 1 benzyl 4- (8-(tert-butoxycarbonyl)-3,8- diazabicyclo [3.2.1]octan-3-yl)-2-((1-
  • Step 1 benzyl 4- (8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-((1-(((R)-3- fluoropyrrolidin-l-yl)methyl)cyclopropyl)methoxy)-5,7- dihydro-6H-pyrrolo [3,4-d]pyrimidine-6-carboxylate [0293]
  • Step 2 tert-butyl -3- (2-((1-(((R)-3-fluoropyrrolidin-l- yl)methyl)cyclopropyl)methoxy)-6,7-dihydro-5H-pyrrolo [3,4- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • Step 3 tert-butyl (1,8-dibromoisoquinolin-3-yl)carbamate

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Abstract

La présente invention concerne un composé ayant une activité inhibitrice contre la mutation KRAS G12D ou un sel de celui-ci, et concerne une composition pharmaceutique comprenant le composé en tant que principe actif.
PCT/JP2019/049074 2019-11-29 2019-12-06 Composé ayant une activité inhibitrice contre la mutation kras g12d Ceased WO2021106231A1 (fr)

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TW109141900A TW202134243A (zh) 2019-11-29 2020-11-27 對ｋｒａｓ ｇ１２ｄ突變具有抑制活性之化合物
CN202080094483.XA CN115003677B (zh) 2019-11-29 2020-11-27 对kras g12d突变具有抑制活性的化合物
US17/780,597 US20230348495A1 (en) 2019-11-29 2020-11-27 A compound having inhibitory activity against kras g12d mutation
JP2022558819A JP7707189B2 (ja) 2019-11-29 2020-11-27 Ｋｒａｓ ｇ１２ｄ変異に対して阻害活性を有する化合物
PCT/JP2020/045146 WO2021107160A1 (fr) 2019-11-29 2020-11-27 Composé ayant une activité inhibitrice contre la mutation kras g12d
EP20833977.0A EP4065583A1 (fr) 2019-11-29 2020-11-27 Composé ayant une activité inhibitrice contre la mutation kras g12d

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CN115003677A (zh) 2022-09-02
US20230348495A1 (en) 2023-11-02
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